1-chloro-1-methyl-2,2,3,3-tetrafluorocyclobutane for general inhalation anesthetic

ABSTRACT

A new compound, 1-chloro-1-methyl-2,2,3,3tetrafluorocyclobutane, has been found useful as a general inhalation anesthetic.

United States Patent n91 Holdsworth et al.

[451 Aug. 19, 197s [73] Assignee: W. R. Grace & Co., Cambridge,

Mass.

22 Filed: July 26,1974

211 Appl. No.1 492,343

[52] US. Cl. 424/352 [51] lnt. Cl A6lk 27/00 [58] Field of Search 424/352, 79; 260/653.8

[56] References Cited UNITED STATES PATENTS 3,769,429 lO/l973 ONeill et al. 424/352 Primary Examiner-Jer0me D. Goldberg Attorney, Agent, or FirmArmand McMillan; C. E. Parker 5 7 ABSTRACT A new compound, l-chloro-l-methyl-2,2,3,3-tetrafluorocyclobutane, has been found useful as a general inhalation anesthetic.

1 Claim, N0 Drawings l-CHLORO- l -METI-IYL-2.2,3 ,3-TETRA- FLUOROCYCLOBUTANE FOR GENERAL INHALATION ANESTIIETIC THE PRIOR ART Due in part to the unpredictability of the chemical and physiological behavior of organic compounds such as the halogenated alkanes and also to the lack of understanding of the mode of action of anesthetics in genera], the search for new useful anesthetic agents remains beyond the scope of the routine expertise of both the chemist and the physiologist. Thus it is, for instance, that while cyclopropane is an effective if inflammable anesthetic, one of its closely related water insoluble homologs, cyclopentane, has no medical utility. As to cyclobutanes, a recent review of the state of the art [Larsen, E. R., Fluorine Chemistry Reviews, Volume 3, page 1 (l969)] is no more enlightening in its report that of three closely related fluorocyclobutanes, one is said to possess anesthetic properties l ,2-dihydrohexafluoro-) while its more highly halogenated homologs are either toxic 1,2- dichlorohexafluro-) or inactive (octafluro-). Subsequent discoveries in this field have failed to provide reliable guidelines for the identification of new useful substances from the numerous conceivable halogenated cyclobutane structures.

SUMMARY OF THE INVENTION The new compound l-chloro-l-methyl-2,2,3,3-tetrafluorocyclobutane has been found to possess useful properties as a general inhalation anesthetic.

DETAILED DESCRIPTION The compound of this invention can be prepared by cyclizing appropriately selected ethylenic compounds in the presence of certain polymerization inhibitors. The cyclization method has been generally described by Coffman et al [.I. Am. Chem. Soc. 71, 490 (1949)].

EXAMPLE 1 4-t-Butylpyrocatechol, 3.5 parts by weight, was placed in a clean stainless steel autoclave. The apparatus was sealed, checked for leaks, then cooled to approximately 75C with dry ice in methanol. Tetrafluoroethylene, 180 parts, and 2-chloropropylene, 145 parts, were added. The autoclave was then heated at 225C for 8 hours.

The contents of the autoclave were subsequently cooled to room temperature and transferred to a liquid nitrogen trap from which the low boiling fractions were allowed to vent slowly into a fume hood. The reaction mixture obtained was shown by gas chromatography to contain 27.2% of the theoretical quantity of product possible. Further separation and purification of the product was carried out by preparatory scale vapor chromatography to yield a material with a boiling point of 88C and a density of L342 at 20C.

Example 2 The physiological effects of l-chloro-l-methyl- 2,2,3,3,-tetrafluorocyclobutane were demonstrated upon mice using a standard test for evaluation of inha lation anesthetics, similar to that described by Robbins [Pharmacology and Experimental Therapeutics 86, 197 (l946)]. In this test, mice were exposed to the compound for a period of 10 minutes in a rotating drum. Observations were made of the pinch reflex, the corneal reflex and the return of the righting reflex. At least four graded doses were employed to determine the minimum concentration required to anesthetize 50% of the mice (AC;,,,) and the minimum concentration required to kill 50% of the mice (LC The anesthetic index (Al) was then calculated from these minimum concentrations. In this manner, it was found that the cyclobutane of this invention has an AC of 1% and an LC of more than 3% but less than 4%, giving a anesthetic index between 3 and 4.

The compound of the invention is thus a fairly potent material, capable of inducing a state of anesthesia in air-breathing mammals, from which the latter recover, provided that the lethal concentration of anesthetic vapors is not reached.

The compound can be stored in containers of the type commonly used for commercial anesthetics of comparable boiling point. e.g., halothane, and it can be administered by means of apparatus or machines designed to vaporize liquid and mix them with air, oxygen and other gaseous combinations in quantities capable of supporting respiration. It is further contemplated that the compound herein disclosed may be used in admixture with pharamecutially acceptable diluents and stabilizers such as thymol, or in combination with one or more of the known inhalation anesthetics.

What we claim is:

1. The process of inducing anesthesia in a mammal, which comprises administering by inhalation to said mammal an effective quantity, to induce anesthesia, of

l-chlorol -methyl-2,2,3 ,3 ,-tetrafluorocyclobutane. 

1. THE PROCESS OF INDUCING ANESTHESIA IN A MAMMAL, WHICH COMPRISES ADMINISTERING BY INHALATION TO SAID MAMMAL AN EFFECTIVE QUANTITY, TO INDUCE ANESTHESIA, OF 1-CHLORO-1-METHYL2,2,3,3,-TETRAFLUOROCYCLOBUTANE. 